DESCRIPTION: Infection and tissue damage activate nearby cells to produce a group of proteins, called cytokines, which help mediate the resulting inflammatory and repair processes. Interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF1) are often called master cytokines because they are produced by many cell types and have multiple effects on target cells including the synthesis of additional cytokines. The effects of a given cytokine may vary with the target cell type and immediate environment. All three cellular layers of the cornea appear capable of producing and responding to these master cytokines, although the regulation of production and the repertoire of responses are not clear. Knowledge of the roles of these master cytokines in response to corneal insults should enhance the development of methods to manipulate repair and inflammatory processes therapeutically. These novel treatments may then reduce the corneal scarring, cloudiness, ulceration, melting and neovascularization that are major causes of vision loss worldwide. The PI hypothesizes that cytokines are critical mediators of corneal repair. The aims of this proposal are to determine the temporal and spatial patterns of IL-1, IL-6, and TNF2 production in response to ultraviolet radiation or excimer laser transepithelial keratectomy in mice; to use mice with genetic alterations in specific cytokines or their receptors to identify steps in corneal repair of these two types of injury that require one or more of these three cytokines; and to determine the underlying mechanisms by which functional deficiency of IL-1 leads to impaired stromal regeneration and diminished granulocyte infiltration and by which functional deficiency of TNFa leads to decreased UV-induced epithelial erosions.